Table 8 summarizing the data of all preclinical studies in anxiety disorders/MDD/schizophrenia specifying the design, objectives, methodology, results, and conclusion

103

Animal study (CUMS-induced depression mouse model)

Examine the effects of 15-Hz rTMS on glial activation and immune regulatory pathways

Applied 15-Hz rTMS for four weeks. Measured microglia (Iba1 +) and astrocytes (GFAP +) levels in the hippocampus (CA1, DG) and PFC. Assessed cytokines (IL-6, IL-1β, TNF-α) and TLR4/NF-kB/NLRP3 pathway

Microglia reduced in hippocampus and PFC. Astrocytes increased. Cytokine levels decreased, and TLR4/NF-kB/NLRP3 pathway restored

15-Hz rTMS reduces microglial activation, modulates immune pathways, and may offer therapeutic benefits in MDD

104

Animal study (Gunn rats with ECS)

Evaluate ECS (ECT alternative) on microglial and astroglial activation in schizophrenia-like behavior

ECS administered. Levels of CD11b and GFAP measured in hippocampus

ECS lowered CD11b and GFAP levels, reducing glial activation in the hippocampus

ECS decreases neuroinflammation and glial activation, showing potential for schizophrenia treatment

105

Animal study (EAE model)

Investigate the effects of ECS on neuroinflammation, immune cell infiltration, and adaptive immune responses

ECS treatment analyzed for CNS neuroinflammation, spinal immune cell infiltration, and adaptive immune response markers (T-cell, Iba1, NG2 + oligodendrocyte progenitor cells)

Reduced microglial neurotoxicity and neuroinflammation. Decreased immune cell infiltration and axonal loss without affecting adaptive immune responses

ECS reduces chronic CNS neuroinflammation, demonstrating promise for treating neuroinflammatory diseases

106

Animal study (EAE mouse model)

Examine rTMS effects on anxiety disorders, MDD, and astrocyte activity in an EAE model

Applied rTMS. Measured astrocyte markers (GFAP, C3 d) in hippocampus (CA1, CA3, DG). Evaluated behavioral outcomes for anxiety disorders and MDD

Anxiety disorders and MDD alleviated. Astrocyte activity downregulated, aligning with findings in depressed-MS patients with elevated serum GFAP levels

rTMS inhibits neurotoxic reactive astrocytes, suggesting potential as a therapy for MS patients with MDD

107

Human and animal study

Assess ECT effects on inflammation and blood cell ratios in MDD

Analyzed NLR, PLR, SII, and depression scores in ECT patients. Correlated blood ratios with treatment response and cognitive effects

NLR, PLR, SII higher in psychotic and late-onset MDD. Negative correlation between blood ratios and depression scores. Higher blood ratios linked to worse cognitive effects post-ECT

Peripheral inflammation influences severity and post-ECT recovery, offering insights into personalized treatment strategies

108

Animal study (antidepressant-resistant rats)

Investigate DBS effects on immune function via mTOR pathway modulation

Chronic NAc DBS applied. Measured expression of phospho-GSK3β and phospho-mTOR in hippocampal regions

Upregulated phospho-GSK3β and phospho-mTOR in infralimbic and ventral hippocampus, indicating immune function modulation

DBS impacts immune regulation through mTOR, providing potential for treatment-resistant MDD

109

Animal study (LPS-induced inflammation model)

Explore anti-inflammatory reflex mechanisms and IL-6-dependent signaling in immune response regulation

LPS injection with vagal nerve stimulation or nicotinic α7 receptor agonist treatment. Assessed IL-6 trans-signaling effects on inhibitory post-synaptic current (IPCS) in mPFC

IL-6-induced IPCS amplitude decrease was prevented by JAK/STAT and GSK3β signaling. Anti-inflammatory reflex impeded LPS hyperexcitability. Upregulated IPCS saturation current in sgp130 Fc GFAP mice

IL-6 and GABAergic signaling play critical roles in stress-induced pathological conditions, with sgp130 Fc offering therapeutic potential